This project is designed to use positron emission tomography (PET) to investigate the functional linkage of neurotransmitter systems. Specifically, it will focus on the interactions of dopamine and serotonin since both systems have been implicated in schizophrenia, depression and affective disorders. The applicants will use PET to quantify the responsiveness of dopaminergic and serotonergic systems to specific pharmacologic challenges. These studies will use C-11 raclopride (RAC), a D2/D3 receptor antagonist, to image postsynaptic dopamine receptors and a new ligand, C-11 SR46349B, a serotonin (5-HT2) antagonist. By observing dose response and time course of events, the ability of PET to quantify pharmacologic activity will be validated by assessing the following: (1) the sensitivity of the response at different challenge doses, (2) the reproducibility of response, (3) the stability of the baseline measurement and (4) the time course of response to the challenge. Also the effect of anesthesia on these interactions will be investigated. Finally, findings in non-human primates will be confirmed by using in vivo microdialysis in freely moving rats to study changes in endogenous neurotransmitter levels.